This invention relates to 4,5-diaryl-2-substituted thioimidazoles as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT), processes for their preparation, and use as antihypercholesterolemic agents.
Hypercholesterolemia is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells is esterified by ACAT prior to its incorporation and secretion into the bloodstream as chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol.
Lautenschlgager et al. in U.S. Pat. No. 4,654,358 disclose imidazol-2-yl mercapto alkanoic acids having the formula ##STR2## and a process for the treatment of humans suffering from inflammatory diseases or diseases in relation with the lipid metabolism
wherein
k is the numeral 0, 1 or 2,
R.sup.1, R.sup.2 and R.sup.3 which are the same or different from each other, are a member selected from the group consisting of hydrogen, fluorine, chlorine, methyl, methoxy and trifluoromethyl,
R.sup.4 is a member selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, propyl, isopropyl and butyl, and
A is a member selected from the group consisting of the groups ##STR3## wherein m is zero or a numeral from 1 to 8 and n is a numeral from 2 to 10.
Niedballa et al. in U.S. Pat. No. 4,355,039 describe imidazole derivatives of the formula ##STR4## wherein
Ar.sup.1 and Ar.sup.2 are each phenyl; phenyl substituted by halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.2-6 dialkylamino; pyridyl; furyl; or thienyl; with the proviso that Ar.sub.1 and Ar.sub.2 are not both unsubstituted phenyl;
R.sup.1 is hydrogen, C.sub.1-4 alkly or C.sub.1-4 alkyl substituted by hydroxy, C.sub.1-4 alkoxy or C.sub.1-6 alkanoyloxy;
n is 0, 1 or 2; and
Z is a C.sub.2-6 -alkyl or -alkenyl residue substituted by one or two of hydroxy, C.sub.1-4 alkoxy, C.sub.2-8 alkylenedioxy, C.sub.1-6 alkanoyloxy or benzolyloxy, or by one alkoxycarbonyl group;
and the salts thereof with physiologically acceptable acids, possess valuable pharmacological properties, e.g., anti-inflammatory activity.
Niedballa et al. in U.S. Pat. No. 4,402,960 describe imidazole derivatives of the formula ##STR5## wherein
Ar.sup.1 and Ar.sup.2 each independently is phenyl, optionally substituted by halogen atoms, alkyl residues, alkoxy residues; or dialkylamino residues; pyridyl, furyl; or thienyl;
R.sup.1 is hydrogen; alkyl of 1-6 carbon atoms optionally substituted by hydroxy groups, alkoxy groups, or acyloxy groups; benzyl; tetrahydropyran-2-yl; or tetrahydrofuran-2-yl;
n is 0, 1 or 2 ; and
Z is phenyl optionally substituted by halogen atoms, alkyl groups, alkoxy groups, nitro groups, amino, acylamino groups or trifluoromethyl groups; pyridyl; N-oxypyridyl; pyrimidinyl; thiazolyl; or thienyl, and the physiologically acceptable salts thereof with acids, have valuable pharmacological activity, e.g., anti-inflammatory activity.
Lautenschlager et al. in U.S. Pat. No. 4,460,598 describe new triphenylimidazolyloxyalkanoic acids of the general formula ##STR6## and a process for the treatment of thromboembolic inflammatory and/or atherosclerotic diseases in humans by using the same wherein n denotes an integer from 1 to 10, while R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 which are identical or different from each other, are members selected from the group consisting of hydrogen, the halogens, alkyl, preferably C.sub.1-4 -alkoxy, and trifluoromethyl, and one or several of the groupments R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, and R.sup.5 and R.sup.6 together, a methylenedioxy group. Particularly suitable and, therefor, preferred are hydrogen, methyl, ethyl, n- and isopropyl, fluorine, chlorine, bromine, methoxy and ethoxy, hydrogen being most preferred. R.sup.7 is a member selected from the group consisting of hydrogen, the alkali metal ions, the straight-chain or branched alkyl group with 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, and the benzyl group. The methyl and the ethyl groups being the preferred alkyl groups.
Ferrini et al. in U.S. Pat. No. 4,308,277 describe compounds of the formula ##STR7## in which R.sup.1 and R.sup.2 independently of one another are substituted or unsubstituted aryl or hetero-aryl groups, R.sup.3 is hydrogen or lower alkyl and R.sup.4 is a substituted or unsubstituted aliphatic hydrocarbon radical (i.e., of lower carbon atom content), and their pharmaceutically usable salts. These compounds possess immunoregulatory, antithrombotic and antiinflammatory properties and can be used as active ingredients in medicaments.
Niedballa et al. in U.S. Pat. No. 4,272,543 describe imidazole derivatives of the formula ##STR8## wherein
AR.sup.1 and AR.sup.2 are independently each phenyl; phenyl substituted by halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.2-6 dialkylamino; pyridyl; furyl; or thienyl; with the proviso that AR.sub.1 and AR.sub.2 are not both unsubstituted phenyl;
R.sup.1 is hydrogen, alkyl of 1-4 carbon atoms or alkyl of 1-4 carbon atoms substituted by hydroxy, C.sub.1-4 alkoxy or C.sub.1-6 alkanoyloxy;
n is 0, 1 or 2; and
Z is cyano; alkynyl of 2-6 carbon atoms; cycloalkyl of 3-8 carbon atoms; cycloalkyl of 3-8 carbon atoms substituted by hydroxy, acyloxy, hydroxymethyl or acyloxymethyl, "acyl" in both cases being the acyl group of a hydrocarbon, aliphatic C.sub.1-6 carboxylic acid or of benzoic acid; or alkyl or 1-4 carbon atoms substituted by cyano, phenyl or cycloalkyl of 3-6 carbon atoms;
or physiologically acceptable salts thereof with an acid, have valuable pharmacological properties (antiinflammatory, antiallergic and immunostimulating activity).
Cherkofsky et al. in U.S. Pat. No. 4,182,769 describe compounds of the formula ##STR9## where
n=0, 1, or 2;
R.sup.1 =C.sub.1 -C.sub.6 alkyl; allyl; vinyl; --CH.sub.2 COCH.sub.3 ; --CH.sub.2 S(O).sub.m, CH.sub.3, where m=0, 1 or 2; mono- and polyhalo C.sub.1 -C.sub.4 alkyl;
R.sup.2 and R.sup.3, the same or different = ##STR10##
Y.sup.1 and Y.sup.2, the same or different=hydrogen, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, Cl, F, CF.sub.3, NH.sub.2, --N(CH.sub.3).sub.2, NO.sub.2, CH.sub.3 S--, CH.sub.3 SO.sub.2 --, or Y.sub.1 and Y.sub.2 taken together forming a dioxymethylene brige; provided when R.sup.1 =C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.4 haloalkyl with halogen substituted at the 3 or 4 position, allyl, or acetonyl, both Y.sup.1 and Y.sup.2 cannot be H;
R.sup.4 =C.sub.1 -C.sub.6 alkyl, allyl, CH.sub.2 CH.sub.2 N(R.sup.5).sub.2, ##STR11## 2-tetrahydropyranyl, 2-tetrahydrofuranyl, and many additional groups other than H. These compounds are useful for treating arthritis and related diseases.
Doebel et al. in U.S. Pat. No. 3,636,003 describe certain derivatives of 2-mercaptoimidazole which have anti-inflammatory utility. These compounds have the formula ##STR12## wherein
R.sup.1 is lower alkyl, phenyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R.sup.2 is hydroxy or lower alkoxy;
R.sup.3 is hydrogen or lower alkyl;
R.sup.4 is lower alkyl, phenyl or phenyl substituted; lower alkyl, lower alkoxy, halogen or trifluoromethyl; and
n is 0 or 1.
Doebel et al. in U.S. Pat. No. 3,488,423 describe a process for producing antiinflammatory effects in warm-blooded animals by administering to them certain derivatives of 2-mercaptoimidazole in effective amounts. The compounds useful in the claimed process can be represented by the following structural formula: ##STR13## wherein
R.sup.1 is lower alkyl; lower alkenyl; cycloalkyl; cycloalkyl-lower-alkyl; monocarbocyclic aryl; mono-carbocyclic aryl-lower-alkyl; di-lower-alkylamino-lower-alkyl; lower alkoxy-lower-alkyl; or pyridyl;
R.sup.2 represents hydrogen, di-lower-alkylamino-lower-alkyl, carbo(lower)alkoxy or lower alkylcarboxy;
R.sup.3 stands for hydrogen or lower alkyl, and
R.sup.4 denotes hydrogen, lower alkyl or monocarbocyclic aryl.